Damaged Cell ‘Trash Cans’ May Contribute to Parkinson’s Disease

Scientists have uncovered more than 20 genes whose mutations cause familial forms of Parkinson’s disease. One of these genes is known as VPS13C, and mutations in this gene may contribute to the disease’s onset by causing the “trash cans” of cells to malfunction, Yale researchers report in a new study. Their findings—which could have implications for new therapeutic targets for Parkinson’s disease—were published April 10 in Nature Cell Biology.

Several of the genes associated with Parkinson’s disease are involved in the regulation of lysosomes. These cellular organelles serve as the garbage cans of the cell, accumulating and breaking down waste products and recycling their components. Lysosomal dysfunction may lead to the leakage of toxic substances within brain cells, thus contributing to the onset of Parkinson’s disease.

Pietro De Camilli, MD, John Klingenstein Professor of Neuroscience, professor of cell biology, and Howard Hughes Medical Institute Investigator at Yale School of Medicine (YSM), and his team study the gene VPS13C, which codes for a protein responsible for transferring lipids between organelles. Mutations in VPS13C cause or increase the risk of developing Parkinson’s disease.

As De Camilli and collaborators have previously shown, the VPS13C protein acts as a bridge that transfers lipids from the endoplasmic reticulum—a network of membranes that plays a crucial role in lipid production—to lysosomes. In the latest study they found that when lysosome membranes were damaged, VPS13C proteins rapidly rushed to them, likely to funnel in lipids, an important process in their repair.

These findings suggest that leakage of lysosomal content may be an explanation for why mutations that cause the loss of function of the VPS13C gene are associated with Parkinson’s disease.

“Imagine a fire truck rushing to the scene to minimize damage—this mechanism is part of an emergency system that prevents leakage from a damaged lysosome,” says De Camilli, who is the paper’s senior author. “A chronic loss of lysosomal integrity could lead to cell toxicity and ultimately neurodegeneration.”

For the study, De Camilli and his team cultured cells in the laboratory and used a gene-editing tool called CRISPR-Cas9 to eliminate the VPS13C gene. Then, they observed how cells responded to a chemical that damages the membrane that encloses lysosomes.

Under normal conditions, most VPS13C proteins are switched off. But, within minutes of lysosome damage, the researchers observed a “dramatic” recruitment of VPS13C proteins to the lysosome, says Xinbo Wang, PhD, associate research scientist and first author of the study. A region of the VPS13C protein is able to recognize the damaged membrane and bind to it, which turns the protein on and allows it to interact with the damaged lysosome. With VPS13C now bound, it serves as a bridge between the damaged lysosome and the endoplasmic reticulum, and lipids can flow across it to help repair the lysosome membrane.

Mutations in the gene LRRK2 are also responsible for Parkinson’s disease, and previous research has shown that these proteins accumulate around damaged lysosomes as well. In the new study, the researchers showed that while VPS13C accumulated rapidly, LRRK2 proteins showed a more delayed response to lysosomal damage, suggesting the two proteins participate in different steps of the lysosome repair process.

“We have two proteins implicated in Parkinson’s disease and both come in to help repair lysosomes, but with different kinetics,” says De Camilli. “One of our key goals in the future is to understand the relationship between these proteins.”

The study’s findings add to the growing evidence that an inability to repair damaged lysosomes may be one mechanism that contributes to Parkinson’s disease. This highlights the importance of future research that investigates ways to protect the integrity of lysosomes within cells.

Going forward, De Camilli’s team aims to better understand the functions of VPS13C proteins. They also hope to study the relationship between VPS13C and other genes associated with Parkinson’s disease. Because the disease is influenced by multiple genetic factors, scientists could potentially learn to treat the condition by therapeutically targeting each gene one at a time. But one of the broader goals in Parkinson’s disease research is to identify cellular processes that are vulnerable to defects in multiple genes.

“If the functions of some of these genes converge on the same process, a therapeutic intervention that fixes the process could work as a magic bullet that prevents the defects generated by multiple genes,” says De Camilli.

As recently as 20 years ago, while some Parkinson’s disease genes had been identified, there was little understanding about the cellular mechanisms underlying Parkinson’s disease, De Camilli says. But he is excited to see how much this field has grown. In 2006, YSM established the interdepartmental program in Cellular Neuroscience, Neurodegeneration, and Repair, which recruited Yale researchers who study the fundamental mechanisms of disease. Then, last year, YSM announced the formation of the Stephen and Denise Adams Center for Parkinson’s Disease Research.

“Parkinson’s disease research is lively and thriving at Yale,” says De Camilli.

Authors of the study also include Shawn Ferguson, PhD, associate professor of cell biology and of neuroscience at YSM, and Dario Alessi, PhD, professor of signal transduction at University of Dundee in the United Kingdom.

This work was supported in part by grants from the National Institutes of Health (awards DA018343, NS36251, and GM105718). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The work was also supported by the Parkinson’s Foundation, the UK Medical Research Council, and Aligning Science Across Parkinson’s grants through the Michael J. Fox Foundation.